Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. 5% to 15% of the population will have a symptomatic episode of a stone by the age of 70 and at least 50% of these individuals will have recurrent disease. To date, urolithiasis researchers have been limited to cell culure studies or a rat model where hyperoxaluria is induced by either ethylene glycol oral administration that is toxic to multiple organs or by high dose intraperitoneal sodium oxalate injection. The levels of induced urinary oxalate excretion in the rat needed to produce oxalate crystalluria and tisssue or cell response are criticized as being supraphysiologic compared to man. We propose that the pig is ideal for the development of an animal model of calcium oxalate crystalluria and calcium oxalate stone disease. The anatomy and physiology of the pig kidney is very similar to man. The anerobic bacteria Oxalobacter formigenes degrades oxalate to formate in the pig gut and normally stops the pig from becoming hyperoxaluric. We have successfully obtained Oxalobacter formigenes free pigs and report here for the first time that these pigs demonstrated a significant increase in urinary oxalate excretion as the result of an oral oxalate load similar to that experienced by man ingesting an oxalate rich diet. We propose to induce hyperoxaluria in the pig by feeding them an oxalate rich diet. We propose to study the effect of hyperoxaluria on pig kidney physiology and its impact on calcium oxalate crystal attachment and stone maturation. We hypothesize that pigs fed oxalate will form calcium oxalate crystalluria and calcium oxalate stones in their urinary tract in a manner very similar to man. We also hypothesize that these hyperoxaluric pigs are ideally suited for the extension of studies on the effect of hyperoxaluria on renal epithelial cell physiology, crystal attachment and stone maturation. This grant proposal contains three Specific Aims that test our hypotheses:Specific Aim I: To develop a new hyperoxaluric pig animal model.Specific Aim II: To initiate calcium oxalate crystalluria in the pig and to identify the site of crystal attachment along the nephron.Specific Aim III: To induce calcium oxalate stone disease in the pig and to characterize the process of stone maturation. These Specific Aims and their associated questions will allow us to fully describe the development of hyperoxaluria in the pig and the development of calcium oxalate crystalluria and calcium oxalate stones. The hyperoxaluric pig will have great potential in the advancement of many areas of urolithiasis research and in the design of new therapeutic modalities for the treatment of stone disease.